Please use this identifier to cite or link to this item: https://hdl.handle.net/10316/109769
Title: Silencing mutant ataxin-3 rescues motor deficits and neuropathology in Machado-Joseph disease transgenic mice
Authors: Nóbrega, Clévio 
Nascimento-Ferreira, Isabel 
Onofre, Isabel 
Albuquerque, David 
Hirai, Hirokazu
Déglon, Nicole 
Almeida, Luís Pereira de 
Issue Date: 2013
Publisher: Public Library of Science
Project: PTDC/SAU-NEU/099307/2008 
PTDC/SAU-FAR/116535/ 2010 
Center for Science and Technology of Madeira (CN) 
National Ataxia Foundation and the Richard Chin and Lily Lock Machado-Joseph disease Research Fund 
Serial title, monograph or event: PLoS ONE
Volume: 8
Issue: 1
Abstract: Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly-inherited neurodegenerative disorder caused by the over-repetition of a CAG codon in the MJD1 gene. This expansion translates into a polyglutamine tract that confers a toxic gain-of-function to the mutant protein--ataxin-3, leading to neurodegeneration in specific brain regions, with particular severity in the cerebellum. No treatment able to modify the disease progression is available. However, gene silencing by RNA interference has shown promising results. Therefore, in this study we investigated whether lentiviral-mediated allele-specific silencing of the mutant ataxin-3 gene, after disease onset, would rescue the motor behavior deficits and neuropathological features in a severely impaired transgenic mouse model of MJD. For this purpose, we injected lentiviral vectors encoding allele-specific silencing-sequences (shAtx3) into the cerebellum of diseased transgenic mice expressing the targeted C-variant of mutant ataxin-3 present in 70% of MJD patients. This variation permits to discriminate between the wild-type and mutant forms, maintaining the normal function of the wild-type allele and silencing only the mutant form. Quantitative analysis of rotarod performance, footprint and activity patterns revealed significant and robust alleviation of gait, balance (average 3-fold increase of rotarod test time), locomotor and exploratory activity impairments in shAtx3-injected mice, as compared to control ones injected with shGFP. An important improvement of neuropathology was also observed, regarding the number of intranuclear inclusions, calbindin and DARPP-32 immunoreactivity, fluorojade B and Golgi staining and molecular and granular layers thickness. These data demonstrate for the first time the efficacy of gene silencing in blocking the MJD-associated motor-behavior and neuropathological abnormalities after the onset of the disease, supporting the use of this strategy for therapy of MJD.
URI: https://hdl.handle.net/10316/109769
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0052396
Rights: openAccess
Appears in Collections:FCTUC Ciências da Vida - Artigos em Revistas Internacionais
FFUC- Artigos em Revistas Internacionais
I&D CNC - Artigos em Revistas Internacionais

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